|Ahead of print
Metronomic chemotherapy for scheduling oral cancer surgery during the COVID-19 pandemic
Shiv Rajan, Vijay Kumar, Naseem Akhtar, Sameer Gupta, Arun Chaturvedi
Department of Surgical Oncology, King George's Medical University, Lucknow, Uttar Pradesh, India
|Date of Submission||27-May-2020|
|Date of Decision||16-Jul-2020|
|Date of Acceptance||24-Jul-2020|
|Date of Web Publication||14-Sep-2020|
Department of Surgical Oncology, King George's Medical University, Lucknow, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Worldwide, hospitals are facing problems in managing cancer patients during the ongoing COVID-19 pandemic. Given the immense cancer burden of oral cancer in India, scheduling surgeries are becoming increasingly difficult. Upfront surgeries are recommended for curative treatment of oral cancers and postponing them raises the fear of progression. Metronomic chemotherapy can be considered during the waiting period given its potential oncological benefits and ease of administration without much toxicity.
Keywords: COVID-19, corona virus, oral cancer, neoadjuvant chemotherapy, metronomic chemotherapy
|How to cite this URL:|
Rajan S, Kumar V, Akhtar N, Gupta S, Chaturvedi A. Metronomic chemotherapy for scheduling oral cancer surgery during the COVID-19 pandemic. Indian J Cancer [Epub ahead of print] [cited 2020 Sep 28]. Available from: http://www.indianjcancer.com/preprintarticle.asp?id=295075
Upfront surgery is the recommended treatment modality for operable oral cavity cancers. Due to the multidimensional effects of the pandemic on health-care system, number of patients being operated has drastically gone down. There is a growing concern of disease progression and the possibility of disease becoming unresectable during this waiting time. This shall significantly impact the quality of life and overall survival. As surgeons, we are trying to find a way to tackle this situation on a case-by-case basis. But at the same point, fear of not receiving treatment on time is affecting patients, and their families. Similar problems are faced for patients undergoing conventional chemotherapy. Immunosuppression and potential risks of getting coronavirus disease-2019 (COVID-19) are additional concerns with chemotherapy.
We encounter a major burden of operable oral cancer in our Out Patient Department of Surgical Oncology at King George's Medical College, Lucknow. Scheduling timely surgery for these patients becomes a juggling act. Given this situation, we have started using metronomic chemotherapy (MC). MC is defined as chronic, equally spaced administration of low doses of chemotherapy drugs without an extended period of rest. Potential oncologic benefits include prevention of tumor progression while ensuring it remains resectable until surgery is scheduled. Patient-related benefits include home-based administration, reduced cost of treatment, no need for intravenous route, least treatment toxicity, better compliance, and ease of patient follow-up by telecommunication.
Our purpose is to 'buy time'- preventing the progression of disease during this waiting period of surgery and to allay the patient's fear of disease progression. We have seen encouraging results of this strategy, laconically termed as 'NABT'––Neoadjuvant Buying Time chemotherapy by us. We have extended this experience of MC to the patients whose surgery deferred due to ongoing pandemic.
Which are the patients to be chosen for the NABT strategy?
Patients who are on long surgical waiting list are suitable for this strategy. Generally, in clinical practice, a period of more than 3 weeks is considered long waiting for cancer surgery; the reasons could be situations like the ongoing COVID-19 pandemic, logistic issues, high patient burden, especially in tertiary care referral centers, and late availability of surgical material procured under Government of India schemes like Ayushman Bharat Yojna/Government funds.
How many months of NABT have been tried before and how long can we do this?
Pai et al. had tried oral MC in neoadjuvant setting for a period ranging from 3 to 12 months and continued until a day before surgery. Kina et al. have used this strategy for 3 weeks before surgery and stopped 1 week before planned surgery [Table 1]. We usually give MC for 1–2 months, which is the usual waiting time in our institute for surgery and stop 1 week before the surgery.
|Table 1: Neoadjuvant metronomic chemotherapy in oral squamous cell cancer|
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Is there a point beyond which it will not produce a further response?
There are limits to response for all chemotherapy drugs. Some patients respond very well and have a complete response whereas some patients progress. Majority of patients have partial response. The same is true for MC. The optimal point beyond which conventional chemotherapy regimens will stop producing meaningful response in neoadjuvant setting for oral squamous cell cancer (OSCC) is still unknown. Similarly, there is a point where the tumor stops responding to MC, which cannot be predicted. In palliative setting, it could be continued till disease progression.
What happens when someone does not respond to NABT?
We have observed that nearly 70% of our patients have a partial response or static disease for at least 2 months or up to the time they are taken up for surgery (unpublished data). In a clinical situation, where NABT with metronomic scheduling does not show a clinical response, there are limited options 1. Schedule the patient for curative surgery (preferred). 2. Give conventional chemotherapy. Clinical examination is important during the NABT to identify the non-responders and plan the subsequent treatment accordingly. However, NABT is not given in anticipation of a response. The aim of NABT was to prevent progression of tumors during the waiting period for surgery.
What is the safety of surgery after NABT?
There is only one study by Pai et al., which looked at the safety of surgery after neoadjuvant MC in oral cancer patients. Authors did not find any significant postoperative complications or wound healing issues. Similarly, we have not faced any significant adverse events as the toxicity is low and drugs are stopped at least 1 week before surgery.
Expected response rates from conventional chemotherapy drugs and metronomic chemotherapy in head neck squamous cell cancer (HNSCC)
MC has been evaluated in HNSCC in different scenarios. The aim of MC in neoadjuvant setting is to prevent disease progression, induce tumor regression (response) and to ensure that disease remains operable while waiting for surgery. Rationale of using MC during the maintenance phase is to improve loco-regional control and disease-free survival. In recurrent setting, MCs have been tried to overcome treatment resistance of conventional chemotherapy by affecting the tumor microenvironment. [Table 2] shows the expected response rates with conventional chemotherapeutic agents (single, double or triple-drug regimen) and oral MC in HNSCC.
|Table 2: Response rates from various chemotherapy drugs in head neck squamous cell cancer|
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Toxicity of metronomic chemotherapy
Better compliance and tolerability are the strengths of MC. In the neoadjuvant setting, not a single patient discontinued MC and there was no mortality, which is extremely encouraging in routine practice and strengthens the idea of safe administration of these drugs at home [Table 1]. Compared to this, with conventional dosing Patil et al., reported that 15.8% of patients discontinued induction chemotherapy after the first cycle. The reasons for discontinuation were mainly logistic issues, but toxicity was an issue in 0.7% of patients. Although considered safe in clinical trial settings, mortality rates as high as 15.3% have been reported with three drugs regimen of taxane, cisplatin, and fluorouracil (TPF) in real-world practice.
The combination of weekly methotrexate and celecoxib had fewer adverse events compared to single-agent cisplatin in recurrent or metastatic HNSCC (18.9% vs 31.4%). Patil et al. carried out quality-adjusted time without toxicity (Q-TWiST) analysis for MC and found lower incidence of grade 3–4 side effects and the duration of these adverse events was short. Overall, it suffices to say that oral MC is well tolerated with better compliance compared to conventional chemotherapy.
The current data suggest the usefulness of oral MC. We propose to consider metronomic scheduling of chemotherapy during this pandemic not as a new standard of care but as a potential strategy to mitigate the uncertainty in the treatment of operable oral cancers. We encourage universal containment efforts for the COVID pandemic and institutional policies to manage OSCC.
We would like to thank our Vice-chancellor Prof MLB Bhatt for his constant academic advice.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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